Although L-dopa treatment is one of the most effective therapies for Parkinson's disease, its long-term use is associated with the development L-dopa-induced dyskinesias or abnormal involuntary movements (AIMs) that can be as disabling as Parkinson's disease itself. Current drug treatments for dyskinesias are very limited and consist primarily of amantadine a drug that is only modestly effective. New therapies for the treatment of L- dopa-induced dyskinesias are therefore critical. Our recent work shows that nicotine treatment reduces L- dopa-induced AIMs in rat, mouse and monkey parkinsonian models. These data across species suggest that nicotine may be of benefit for the treatment of L-dopa-induced dyskinesias. However, nicotine stimulates multiple nicotinic receptors (nAChRs) in the body resulting in the desired response but also unwanted side effects on the cardiovascular, gastrointestinal and other systems. Importantly, the nAChR subtypes in the peripheral and central nervous system are different from one another. Our overall goal is to identify molecular targets among nAChR subtypes to support development of CNS selective therapies for L-dopa-induced dyskinesias. Such knowledge would lead to treatments with optimal efficacy in reducing dyskinesias and a minimum of adverse effects. To approach this, we have two specific aims;the objective of Aim 1 is target identification/validation and that of Aim 2 is pre-clinical proof-of-principle. In Aim 1, we will use nAChR null mutant mice to elucidate the nAChR subtypes involved in the generation of L-dopa-induced dyskinesias. Studies with (-/-) mice offer the advantage that they allows for direct identification of the nAChR population(s) important for the development of L-dopa-induced AIMs. We will use 22, 14, and 16 (-/-) mice since nAChRs containing these subunits are present throughout the CNS and in the nigrostriatal system. These studies will be done in collaboration with Dr. Sharon Grady at the University of Colorado, who currently breeds such mice and their wildtype counterparts. The results of this work will provide a rational basis for the selection of nAChR agonists to test against the development of L-dopa-induced AIMs. Such experiments form the basis of Aim 2, which evaluates the ability of the relevant subtype selective nAChR agonists to reduce L-dopa-induced AIMs. Parkinsonism will also be tested to ensure that drugs with antidyskinetic properties do not worsen motor function. The proposed studies will identify novel nAChR targets for therapeutic intervention to reduce L-dopa- induced dyskinesias in Parkinson's disease. This work is highly translational as it forms a crucial first step for developing nAChR-directed ligands with the greatest potential for reducing dyskinesias. Subsequent steps, which are beyond the scope of this proposal, will be to test these drugs in pre-clinical studies, and eventually in a clinical setting, for their effectiveness in the treatment of L-dopa-induced dyskinesias for Parkinson's disease. PUBLIC HEALTH RELEVANCE: Our data show that nicotine administration reduces L-dopa-induced dyskinesias in several different parkinsonian animal models, including monkeys, rats and mice. Our objective is to identify the nicotinic receptor subtypes that mediate nicotine's antidyskinetic effect using two approaches, nicotinic receptor null mutant mice and nicotinic receptor subtype selective agonists. These studies have the potential to open up a new research direction for the treatment of dyskinesias in Parkinson's disease using drugs targeted to the nicotinic cholinergic system.